Cytosolic Release of Mitochondrial DNA and Associated cGAS Signaling Mediates Radiation-Induced Hematopoietic Injury of Mice.
Hua GuanWen ZhangDafei XieYuehua NieShi ChenXiaoya SunHongling ZhaoXiaochang LiuHua WangXin HuangChenjun BaiBo HuangPing-Kun ZhouShan-Shan GaoPublished in: International journal of molecular sciences (2023)
Mitochondrion is an important organelle of eukaryotic cells and a critical target of ionizing radiation (IR) outside the nucleus. The biological significance and mechanism of the non-target effect originating from mitochondria have received much attention in the field of radiation biology and protection. In this study, we investigated the effect, role, and radioprotective significance of cytosolic mitochondrial DNA (mtDNA) and its associated cGAS signaling on hematopoietic injury induced by IR in vitro culture cells and in vivo total body irradiated mice in this study. The results demonstrated that γ-ray exposure increases the release of mtDNA into the cytosol to activate cGAS signaling pathway, and the voltage-dependent anion channel (VDAC) may contribute to IR-induced mtDNA release. VDAC1 inhibitor DIDS and cGAS synthetase inhibitor can alleviate bone marrow injury and ameliorate hematopoietic suppression induced by IR via protecting hematopoietic stem cells and adjusting subtype distribution of bone marrow cells, such as attenuating the increase of the F4/80 + macrophage proportion in bone marrow cells. The present study provides a new mechanistic explanation for the radiation non-target effect and an alternative technical strategy for the prevention and treatment of hematopoietic acute radiation syndrome.
Keyphrases
- bone marrow
- mitochondrial dna
- induced apoptosis
- copy number
- radiation induced
- signaling pathway
- cell cycle arrest
- stem cells
- mesenchymal stem cells
- endoplasmic reticulum stress
- oxidative stress
- dna methylation
- epithelial mesenchymal transition
- drug induced
- intensive care unit
- cell proliferation
- mass spectrometry
- genome wide
- case report
- atomic force microscopy
- skeletal muscle
- high glucose
- diabetic rats
- high speed
- respiratory failure
- single molecule